MicroRNA-24 antagonism prevents renal ischemia reperfusion injury

Ischemia-reperfusion (I/R) injury of the kidney is a major cause of AKI. MicroRNAs (miRs) are powerful regulators of various diseases. We investigated the role of apoptosis-associated miR-24 in renal I/R injury. miR-24 was upregulated in the kidney after I/R injury of mice and in patients after kidn...

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Published in:Journal of the American Society of Nephrology Vol. 25; no. 12; p. 2717
Main Authors: Lorenzen, Johan M, Kaucsar, Tamas, Schauerte, Celina, Schmitt, Roland, Rong, Song, Hübner, Anika, Scherf, Kristian, Fiedler, Jan, Martino, Filippo, Kumarswamy, Regalla, Kölling, Malte, Sörensen, Inga, Hinz, Hebke, Heineke, Joerg, van Rooij, Eva, Haller, Hermann, Thum, Thomas
Format: Journal Article
Language:English
Published: United States 01.12.2014
Subjects:
Adult
Animals
Apoptosis
Binding Sites
Endothelial Cells - cytology
Endothelium - pathology
Epithelial Cells - metabolism
Female
Gene Silencing
Heme Oxygenase (Decyclizing) - metabolism
Heme Oxygenase-1 - metabolism
Histones - metabolism
Human Umbilical Vein Endothelial Cells
Humans
Inflammation - metabolism
Kidney - metabolism
Kidney - pathology
Kidney Tubules - metabolism
Kidney Tubules - pathology
Male
Mice
MicroRNAs - antagonists & inhibitors
MicroRNAs - genetics
Middle Aged
Receptors, Lysosphingolipid - metabolism
Reperfusion Injury - pathology
heme oxygenase
endothelium
apoptosis
acute renal failure
ischemia-reperfusion
proximal tubule
ISSN:1533-3450, 1533-3450
Online Access:Get more information
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Summary:Ischemia-reperfusion (I/R) injury of the kidney is a major cause of AKI. MicroRNAs (miRs) are powerful regulators of various diseases. We investigated the role of apoptosis-associated miR-24 in renal I/R injury. miR-24 was upregulated in the kidney after I/R injury of mice and in patients after kidney transplantation. Cell-sorting experiments revealed a specific miR-24 enrichment in renal endothelial and tubular epithelial cells after I/R induction. In vitro, anoxia/hypoxia induced an enrichment of miR-24 in endothelial and tubular epithelial cells. Transient overexpression of miR-24 alone induced apoptosis and altered functional parameters in these cells, whereas silencing of miR-24 ameliorated apoptotic responses and rescued functional parameters in hypoxic conditions. miR-24 effects were mediated through regulation of H2A histone family, member X, and heme oxygenase 1, which were experimentally validated as direct miR-24 targets through luciferase reporter assays. In vitro, adenoviral overexpression of miR-24 targets lacking miR-24 binding sites along with miR-24 precursors rescued various functional parameters in endothelial and tubular epithelial cells. In vivo, silencing of miR-24 in mice before I/R injury resulted in a significant improvement in survival and kidney function, a reduction of apoptosis, improved histologic tubular epithelial injury, and less infiltration of inflammatory cells. miR-24 also regulated heme oxygenase 1 and H2A histone family, member X, in vivo. Overall, these results indicate miR-24 promotes renal ischemic injury by stimulating apoptosis in endothelial and tubular epithelial cell. Therefore, miR-24 inhibition may be a promising future therapeutic option in the treatment of patients with ischemic AKI.
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ISSN:1533-3450
1533-3450
DOI:10.1681/ASN.2013121329